Imidazole derivatives having affinity for alpha2 receptors

ABSTRACT

Imidazole derivatives of formula I  
                 
 
     n is 0 or 1  
     R 1  is hydrogen or C 1 -C 4 -alkyl  
     R 2  is hydrogen or R 2  and R 3  together form a double bond  
     R 3  is hydrogen or C 1 -C 4 -alkyl or R 2  and R 3  together form a double bond  
     R 4  is hydrogen, C 1 -C 4 -alkyl, hydroxy or C 1 -C 4 -alkoxy  
     R 5  is hydrogen or C 1 -C 4 -alkyl or R 4  and R 5  together with the carbon atom to which they are attached form a carbonyl group  
     R 6 , R 7  and R 8  are each the same or different and are independently hydrogen, C 1 -C 4 -alkyl or C 2 -C 4 -alkenyl, C 3 -C 7 -cycloalkyl, hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -hydroxyalkyl, thiol, C 1 -C 4 -alkylthio, C 1-4 -alkylthiol, halogen, trifluoromethyl, nitro or optionally substituted amino  
     X is —CHR 9 —(CHR 10 ) m — 
     m is 0 or 1  
     and R 9  and R 10  are each the same or different and are independently hydrogen or C 1 -C 4 -alkyl;  
     or a pharmaceutically acceptable ester or salt thereof, their preparation, use and pharmaceutical compositions comprising them are described. The compounds have affinity for alpha2 receptors and are useful e.g. in the treatment of hypertension, glaucoma, chronic or acute pain, migraine, diarrhea, common cold, ischemia, addiction to chemical substances, anxiety, especially preoperative anxiety and different neurological, musculoskeletal, psychiatric and cognition disorders or as adjuncts to anesthesia.

[0001] The present invention relates to substituted 4(5)-(1-indanyl and1-indanylmethyl and 1-indanylmethylen)imidazoles and4(5)-[1-(1,2,3,4-tetrahydronaphthyl and 1,2,3,4-tetrahydronaphthylmethyland 1,2,3,4-tetrahydronaphthylmethylen]imidazoles and to their isomers,pharmaceutically acceptable salts and esters. It also relates to theirpreparation, use and to pharmaceutical compositions containing them.

[0002] The compounds of the invention have affinity for alpha2 receptorsmost of them being very selective alpha2 agonists. Accordingly, they areuseful in the treatment of hypertension, glaucoma, migraine, diarrhea,ischemia, addiction to chemical substances (such as tobacco andnarcotics) and different neurological, musculoskeletal, psychiatric andcognition disorders as well as sedative and analgesic agents, nasaldecongestants, and adjuncts to anaesthesia.

[0003] Gregory G. B., et al describe in J. Org. Chem. (1990), 55,1479-1483 a new synthesis step for1-phenylalkyl-1-(4-imidazolyl)-1,2,3,4-tetrahydronaphthalene derivativeswhich are useful as nonpeptide antagonists of the angiotensin IIreceptor.

[0004] The imidazole derivatives of the invention are either compoundsof formula I

[0005] n is 0 or 1

[0006] R₁ is hydrogen or C₁-C₄-alkyl

[0007] R₂ is hydrogen or R₂ and R₃ together form a double bond

[0008] R₃ is hydrogen or C₁-C₄-alkyl or R₂ and R₃ together form a doublebond

[0009] R₄ is hydrogen, C₁-C₄-alkyl, hydroxy or C₁-C₄-alkoxy

[0010] R₅ is hydrogen or C₁-C₄-alkyl or R₄ and R₅ together with thecarbon atom to which they are attached form a carbonyl group

[0011] R₆, R₇ and R₈ are each the same or different and areindependently hydrogen, C₁-C₄-alkyl or C₂-C₄-alkenyl, C₃-C₇-cycloalkyl,hydroxy, C₁-C₄-alkoxy, C₁-C₄-hydroxyalkyl, thiol, C₁₋₄-alkylthio,C₁₋₄-alkylthiol, halogen, trifluoromethyl, nitro or optionallysubstituted amino

[0012] X is —CHR₉—(CHR₁₀)_(m)—

[0013] m is 0 or 1

[0014] and R₉ and R₁₀ are each the same or different and areindependently hydrogen or C₁-C₄-alkyl;

[0015] or a pharmaceutically acceptable ester or salt thereof.

[0016] The terms as employed herein have the following meanings: Ahalogen is e.g. chlorine, bromine or fluorine, preferably it is chlorineor fluorine. The C₁-C₄-alkyl, C₁-C₄-alkoxy and C₂-C₄-alkenyl etc. groupsmay be branched or straight chain groups. C₃-C₇-Cycloalkyl is asaturated cyclic hydrocarbon group having preferably 3 to 5 carbonatoms. Optionally substituted amino is an amino group which isunsubstituted or substituted with a C₁-C₄-alkyl group.

[0017] When m=n=0

[0018] R₃ is preferably hydrogen,

[0019] R₄ is preferably hydrogen, hydroxy or C₁-C₄-alkoxy, such asethoxy,

[0020] R₅ is preferably hydrogen, or R₄ and R₅ form, together with thecarbon atom to which they are attached, a carbonyl group.

[0021] R₆ is preferably hydrogen, C₁-C₄-alkyl or C₁-C₄-alkoxy, such asmethyl, ethyl, t-butyl, methoxy or hydroxy. For example, R₆ may beC₁-C₄-alkyl at position 4, 5 or 6, a C₁-C₄-alkoxy at position 5, 6 or 7,or hydroxy at position 5 or position 7.

[0022] More preferably R₆ is hydrogen, 4-methyl, 6-methyl or 7-methoxy.

[0023] R₇ is preferably at position 5, 6 or 7.

[0024] R₇ is preferably hydrogen or C₁-C₄-alkyl, such as, for examplemethyl or t-butyl. For example R₇ may be a C₁-C₄-alkyl at position 5, 6or 7, such as 5-methyl, 7-methyl or 6-t-butyl.

[0025] More preferably R₇ is hydrogen.

[0026] R₈ is preferably at position 6 or 7.

[0027] R₈ is preferably hydrogen, hydroxy or C₁-C₄-alkoxy, such asmethoxy. For example, R₈ may be a C₁-C₄-alkoxy at position 6, such as6-methoxy, or 6-hydroxy or 7-hydroxy.

[0028] R₉ is preferably hydrogen or methyl.

[0029] When n=1 and m=0

[0030] R₁ is preferably hydrogen or methyl.

[0031] R₂, R₃, R₄, R₅ and R₉ are preferably hydrogen,

[0032] R₆ is preferably hydrogen, halogen, C₁-C₄-alkyl, C₁-C₄-alkoxy,such as, for example, methyl or t-butyl, methoxy or hydroxy. R₆ ispreferably at position 4, 5 or 6. For example, R₆ may be a C₁-C₄-alkylat position 4, 5 or 6, such as 4- or 5-methyl or 5-t-butyl or aC₁-C₄-alkoxy at position 5 or 6, such as 5- or 6-methoxy, or 4-, 5- or6-hydroxy. R₆ may be halogen at position 5 or 6, such as 5- or 6-fluoro.

[0033] More preferably R₆ is 4-, 5- or 6-hydroxy.

[0034] R₇ is preferably at position 5, 6 or 7.

[0035] R₇ is preferably hydrogen, C₁-C₄-alkyl, C₁-C₄-alkoxy or hydroxyl.For example, R₇ may be C₁-C₄-alkyl at position 5, 6 or 7, such as 5- or7-methyl or 5- or 6-t-butyl or C₁-C₄-alkoxy at position 6, such as6-methoxy, or 6-hydroxy.

[0036] More preferably R₇ is hydrogen or 6-hydroxy or 6-t-butyl.

[0037] R₈ is preferably at position 6 or 7.

[0038] R₈ is preferably hydrogen, hydroxy, C₁-C₄-alkyl, C₁-C₄-alkoxy,such as methyl or methoxy, for example C₁-C₄-alkyl at position 7, suchas 7-methyl or 7-t-butyl or C₁-C₄-alkoxy at position 6, such as6-methoxy or 6-hydroxy.

[0039] When n=m=1

[0040] R₁, R₂, R₃, R₅, R₈, R₉ and R₁₀ are preferably hydrogen.

[0041] R₄ is preferably hydrogen or C₁-C₄-alkyl, such as, for example,methyl.

[0042] R₆ is preferably at position 5, 6 or 7.

[0043] R₆ is preferably hydrogen, C₁-C₄-alkoxy or hydroxy, for examplemethoxy. For example, R₆ may be 5-, 6- or 7-methoxy, or 6- or 7-hydroxy.

[0044] R₇ is preferably hydrogen or C₁-C₄-alkyl, such as, for example,t-butyl.

[0045] When n=0 and m=1

[0046] R₃, R₄, R₅, R₇, R₈, R₉ and R₁₀ are preferably hydrogen.

[0047] R₆ is preferably hydrogen or halogeN, for example chlorine. R₆may be a halogen at position 5, such as, for example 5-chloro.

[0048] The invention includes within its scope all the possible isomersand stereoisomers, in particular Z and E (cis and trans isomers) andenantiomers.

[0049] The compounds of the formula (I) form acid addition salts withboth organic and inorganic acids. Typical acid addition salts arechlorides, bromides, sulfates, nitrates, phosphates, sulfonates,formates, tartrates, maleates, citrates, benzoates, salicylates,ascorbates. Furthermore, compounds wherein one or more of R₄ to R₈ is ahydroxy group form esters and salts with alkali metals and alkalineearth metals. Typical esters include the lower alkyl esters, such as themethyl, ethyl and propyl esters.

[0050] The compounds of the invention may be prepared using thefollowing methods. (It is to be noted that in the formulae below, whenthe imidazole group is protected, the protecting group R′ (benzyl ortrityl) may be attached to either of the two nitrogen atoms of theimidazole ring. Accordingly, the use of 1-benzyl-5-imidazolecarbaldehydeas starting material leads to 1.5 substituted derivatives whereas whentrityl is used the substitution is mainly 1.4.)

[0051] Synthesis of 4(5)-(1-indanyl)imidazoles and the corresponding4(5)-[1-(1,2,3,4-tetrahydronaphthyl)]imidazoles

[0052] Method a

[0053] Compounds of formula I wherein n=0 and m=0 or 1 may be preparedby an acid catalyzed cyclization of protected or unprotected4(5)-(1-hydroxy-3-phenylpropyl or 1-hydroxy4-phenylbutyl)imidazoles offormulae II and II′, respectively.

[0054] Accordingly, the 4(5)-(1-indanyl)imidazoles may be prepared bycyclization of the compound of formula II

[0055] wherein R₃ to R₉ are as defined above and R′ is a protectinggroup, in the presence of an acid to form the compounds of formula III

[0056] wherein the substituents are as defined above, and removing theprotecting group R′ to form the compounds of formula Ia

[0057] The corresponding 4(5)-[1-(1,2,3,4-tetrahydronaphthyl)]imidazolesmay be prepared by cyclization of the compound of II′

[0058] wherein R₃ to R₁₀ are as defined above I and R′ is a protectinggroup in the presence of an acid to form the compounds of formula III′

[0059] wherein the substituents are as defined above, and removing theprotecting croup R′ to form the compounds of formula Ia′

[0060] wherein the substituents are as defined above.

[0061] The protecting group R′ may be, for example, benzyl or trityl.When R′ is trityl it may be removed using an acid and, when it isbenzyl, by catalytic hydrogenation. The acid used in the cyclizationreaction may be, for example, polyphosphoric acid (PPA) ormethanesulfonic acid.

[0062] The starting materials (compounds of the formulae II and II′,respectively) may be synthesized using different methods. One of them isto prepare α,β-unsaturated ketones through an aldol condensation byallowing an imidazolyl alkyl ketone to react with an appropriatelysubstituted benzaldehyde in the presence of a base:

[0063] The accompanying reduction of carbonyl and the followingcatalytic hydrogenation produces saturated alcohols used in thecyclization. The reduction of the carbonyl group may be performed forexample with sodium borohydride. If the imidazole moiety has beensubstituted with the benzyl group it may also be removed by catalytichydrogenation.

[0064] To accomplish substitution at the position 1 of the indane or1,2,3,4-tetrahydronaphthalene ring it is possible to carry out an1,2-addition reaction of the intermediate ketone with a nucleophilebefore the hydrogenation. This is conveniently perfomed through theGrignard reaction which is carried out by adding to the reaction mixturean alkyl magnesium halide, e.g. bromide, made from alkyl halide andmagnesium:

[0065] Another useful method to produce appropriate alcohols needed asstarting materials in the cyclization is the use of the Grignardreaction in the preparation of 4(5)-(1-hydroxy-phenylalkyl)imidazoles.Here the 4(5)-imidazole carbaldehyde or ketone is allowed to react witha Grignard reagent, prepared from appropriately substituted phenylalkylhalide and magnesium:

[0066] To obtain substitution at the position 3 of the indane group thefollowing procedure may be used: An intermediate of formula Ib, which isalso an active compound wherein R₄ and R₅ together form a carbonylgroup, is prepared.

[0067] There are different methods for the preparation of thisintermediate.

[0068] Firstly, it may be prepared using an acid catalyzed cyclizationof 1-aryl-3-[4(5)-imidazolyl]-α,β-unsaturated-1-propanones:

[0069] The α,β-unsaturated ketone used as the starting material in theabove reaction may be prepared by a base catalyzed aldol condensationfrom substituted or unsubstituted 4(5)-imidazole carbaldehyde and fromappropriately substituted phenyl alkyl ketone.

[0070] Secondly, it may be prepared through the condensation of benzylprotected urocanic acid with an appropriately substituted benzene:

[0071] The benzyl protection is abolished by hydrogenation as describedearlier.

[0072] The ketone group may be then further modified using differentmethods. It may be reduced to the corresponding alcohol with sodiumborohydride or by catalytic hydrogenation, whereafter the alcohol may behydrogenated:

[0073] It is also possible to modify the ketone group using Grignardreaction:

[0074] These compounds may be further transformed to compounds offormula I wherein n=m=0 and R₄ is an alkyl and R₅ is hydrogen bycatalytic hydrogenation as described above.

[0075] The compounds of formula Ib wherein R₄ is alkoxy and R₅ ishydrogen may be prepared from the corresponding alcohol in concentratedhydrochloric acid.

[0076] Method c

[0077] A further method to synthesize the 4(5)-(1-indanyl)imidazoles ofthe formula I is to use the lithiated imidazole in an aromaticelectrophilic substitution reaction with an 1-indanone (imidazole beingbis-protected according to the method described by Kudzma et al. inSynthesis, (1991), p. 1021). The protection may be removed by acidtreatment, which induces the simultaneous loss of water. The double bondis reduced by catalytic hydrogenation as described above.

[0078] Syntehesis of 4(5)-(indan-1-ylmethyl)imidazoles and4(5)-(indan-1-ylmethylen)imidazoles and the correspondingtetrahydronaphthyl derivatives

[0079] Method d

[0080] The preparation of 4(5)(indan-1-ylmethyl andindan-1-ylmethylen)imidazole and the corresponding tetrahydronaphthylskeleton may be accomplished using the so called McMurry reaction, inwhich an imidazole carbaldehyde or ketone reacts with an 1-indanone. Thereaction is catalyzed by low valence titanium. The condensation may befollowed by the hydrogenation of the double bond and simultaneouselimination of the protecting group in the imidazole ring.

[0081] The compounds of the invention may be administered enterally,topically or parenterally. Parenteral administration is used, forexample, when the compounds are given as sedative or anxiolytic agentsin connection to different clinical operations and to cause analgesia orto potentiate anesthesia.

[0082] The compounds of the invention may be formulated alone ortogether with another active ingredient and/or a pharmaceuticallyacceptable diluent or carrier to different pharmaceutical unit dosageforms i.e. tablets, capsules, solutions, emulsions and powders etc.using conventional techniques. The pharmaceutical carriers employed areselected with the planned manner of administration in mind. Thus, solidcarriers may include lactose, sucrose, gelatin and agar, while liquidcarriers typically include waters syrup, peanut oil and olive oil. Theamount of the active ingredient varies from 0.01 to 75 weight-%depending on the type of the dosage form.

[0083] The appropriate oral dosage for the compounds of the inventiondepends on several factors such as the compound to be administrated, thespecies, age and the sex of the subject to be treated, the condition tobe treated and on the method of administration. Accordingly, the dosagefor parenteral administration is typically from 0.5 μg/kg to 10 mg/kgper day and that for oral administration is from 5 μg/kg to 100 mg/kgfor an adult male.

[0084] The invention also provides a compound of the invention or anester or salt thereof for use in a method of treatment of human oranimal body.

[0085] The present invention further provides a compound of theinvention or an ester or salt thereof for use in the treatment ofhypertension, glaucoma, chronic and acute pain, migraine, diarrhea,common cold, ischemia, addiction to chemical substances, anxiety,especially preoperative anxiety and different neurological,musculoskeletal, psychiatric and cognition disorders or as an adjunct toanesthesia.

[0086] The invention also provides the use of a compound of theinvention or an ester or salt thereof in the manufacture of a medicamentfor the treatment of hypertension, glaucoma, chronic and acute pain,migraine, diarrhea, common cold, ischemia, addiction to chemicalsubstances, anxiety, especially preoperative anxiety and differentneurological, musculoskeletal, psychiatric and cognition disorders or asan adjunct to anesthesia.

[0087] The invention further relates to a method for the treatment ofhypertension, glaucoma, chronic and acute pain, migraine, diarrhea,common cold, ischemia, addiction to chemical substances, anxiety,especially preoperative anxiety and different neurological,musculoskeletal, psychiatric and cognition disorders by administering toa subject in need of such treatment an effective amount of the compoundof the invention or a pharmaceutically acceptable ester or salt thereof.

Test Results

[0088] 1. Alpha2 agonism in rat vas deferens model

[0089] Alpha2 agonism was determined by means of isolated, electricallystimulated prostatic portions of rat vas deferens preparation (Virtanenet al. Arch. Int. Pharmacodyn et Ther. 297 (1989), pp. 190-204). In thismodel, an alpha2 agonist is able to inhibit electrically inducedmuscular contractions by activating the presynaptic alpha2 adrenoceptorsand thus diminishing the secretion on the motor transmitter. The knownalpha2 agonist dexmedetomidine was used as reference substance. Resultsare shown in Table 1, where the alpha2 agonist effect is presented asthe pD₂-value (negative logarithm of the molar concentration of thecompound producing 50 percent of maximal inhibition).

[0090] The following compounds were tested:

[0091] 1 4-(4-Methylindan-1-yl)-1H-imidazole hydrochloride

[0092] 2 3-(1H-Imidazol-4-ylmethyl)-indan-5-ol hydrochloride

[0093] 3 4-[1-(Indan-1-yl)-ethyl]-1H-imidazole hydrochloride

[0094] 4 8-(1H-Imidazol-4-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-olhydrochloride

[0095] 5 dexmedetomidine (reference compound) TABLE 1 Alpha2 agonism invitro Compound pD₂-value 1 8.1 + −0.2 2 8.5 + −0.1 3 8.9 + −0.3 4 7.0 +−0.1 5 8.4 + −0.1

[0096] 2. Binding assays

[0097] Affinities for α₂-adrenoceptors and α₁-adrenoceptors wereestimated by determining the displacement of 1 nM ³H-RX821002 (α₂) or0.1 nM ³H-prazosin (α₁) from α-adrenoceptors in rat neocorticalmembranes. For this purpose membranes were incubated with differentconcentrations of test compounds spanning a concentration range of fiveorders of magnitude. Nonspecific binding was defined with 10 μMphentolamine. Membranes were used at a protein concentration of 2 mg/mlin a total volume of 250 μl. The incubation buffer consisted of 50 mMTRIS-HCl, pH 7.7. After a 30 min incubation at 25° C. samples werefiltered through glass fibre filter and filters were washed three timeswith 4 ml icecold wash buffer consisting of 10 mM TRIS-HCl, pH 7.7.Filters were then dried, impregnated with a scintillation cocktail andcounted in a scintillation counter. Experimental data was analyzed usingthe commercial nonlinear least squares computer program LIGAND.

[0098] Each compound was tested in at least three independentexperiments for its affinity on rat neocortical α₂- or α₁-adrenoceptors.The results are shown in Table 2. TABLE 2 Affinity on rat neocorticalα₂- or α₁-adrenoceptors alpha2 vs alpha1 Compound pKi α₂ pKi α₁selectivity 1 8.44 7.31 14 2 8.70 6.61 126 3 8.35 6.21 142 4 7.39 6.85 35 8.42 6.48 90

[0099] The following examples illustrate how compounds of the inventionmay be prepared.

EXAMPLES

[0100] 4-(6-tert-Butylindan-1-yl)-1H-imidazole

[0101] a) 3-(4-tert-Butylphenyl)-1-(1H-imidazol-4-yl)-propan-1-ol

[0102] A solution of 4-tert-butylbenzaldehyde (5.7 g),1-(3-benzyl-3H-imidazol4-yl)-ethanone (7.0 g) and 48% sodium hydroxide(2.0 ml) in methanol (60 ml) is heated at 60-65° C. for 11 hours. Thereaction mixture is then cooled in an ice bath. The resultingprecipitate is filtered and the solid intermediate1-(3-benzyl-3H-imidazol-4-yl)-3-(4-tert-butylphenyl)-propen-1-one isrinsed with methanol. The yield is 10.0 g.

[0103] The intermediate is dissolved in the mixture of ethanol (170 ml)and concentrated hydrochloric acid (3 ml). The reaction mixture ishydrogenated at 50-60° C. with 10% palladium on carbon as catalyst untilno more hydrogen is consumed. The mixture is filtered and the filtrateis evaporated to dryness. The residue is dissolved in water and is madealkaline with sodium hydroxide. The product is then extracted intomethylene chloride which is washed with water, dried with sodium sulfateand evaporated to dryness. The product is converted to its hydrochloridesalt in ethyl acetate using dry hydrochloric acid. The yield is 6.8 g.

[0104]¹H NMR (as HCl-salt, MeOH-d₄): 1.29 (s, 9H), 2.06-2.13 (m, 2H),2.62-2.78 (m, 2H), 4.77 (t, 1H), 7.13 (m, 2H), 7.30 (m, 2H), 7.40 (s,1H), 8.79 (s, 1H)

[0105] b) 4-(6-tert-Butylindan-1-yl)-1H-imidazole

[0106] A mixture of3-(4-tert-butylphenyl)-1-(1H-imidazol4-yl)-propan-1-ol (2.0 g) andmethanesulfonic acid (30 ml) is heated at 60° C. for 5 minutes. Thereaction is then quenched by pouring it into ice-water solution. Theacidic solution is made basic with ammmonium hydroxide solution, andextracted with ethyl acetate. The combined organic layers are washedwith water, dried with sodium sulfate, and evaporated to dryness underreduced pressure. The crude product is purified by flash chromatographyby eluting with methylene chloride-methanol as eluent. The product iscrystallized from ethyl acetate. The yield is 220 mg.

[0107]¹H NMR (MeOH-d₄); 1.24 (s, 9H), 2.07-2.20 (m, 1H), 2.43-2.54 (m,1H), 2.81-3.01 (m, 2H), 4.35 (t, 1H), 6.74 (s, 1H), 7.09 (s, 1H),7.14-7.21 (m, 2H), 7.60 (s, 1H)

[0108] Using the same method the following compounds were prepared:

[0109] 4-(Indan-1-yl)-1H-imidazole

[0110]¹H NMR (CDCl₃) 2.08-2.19 (m, 1H), 2.41-2.51 (m, 1H), 2.80-2.95 (m,2H), 4.37 (t, 1H), 6.65 (s, 1H), 7.07-7.21 (m, 4H); 7.25 (s, 1H)

[0111] 4-(4-Methylindan-1-yl)-1H-imidazole. M.p. of hydrochloride153-156° C.

[0112]¹ H NMR (as HCl-salt, MeOH-d₄): 2.08-2.20 (m, 1H), 2.30 (s, 3H),2.58-2.69 (m, 1H), 2.87-3.10 (m, 2H), 4.59 (t, 1H), 6.89 (d, J=7.0 Hz,1H), 7.05-7.13 (m, 2H), 7.30 (s, 1H), 8.83 (s, 1H)

[0113] 4-(6-Methylindan-1-yl)-1H-imidazole

[0114]¹H NMR (as HCl-salt, MeOH-d₄): 2.07-2.20 (m, 1H), 2.28 (s, 3H),2.55-2.66 (m, 1H), 2.89-3.08 (m, 2H), 4.53 (t, 1H), 6.88 (s, 1H), 7.06(d, J=7.8 Hz, 1H), 7.19 (d, J=7.8 Hz, 1H), 7.30 (s, 1H), 8.79 (s, 1H)

[0115] 4-(6-Ethylindan-1-yl)-1H-imidazole

[0116]¹H NMR (as HCl-salt, MeOH-d₄): 1.17 (t, 3H), 2.08-2.21 (m, 1H),2.55-2.67 (m, 3H), 2.90-3.10 (m, 2H), 4.56 (t, 1H), 6.91 (s, 1H), 7.08(d, J=7.7 Hz, 1H), 7.22 (d, J=7.7 Hz, 1H), 7.32 (s, 1H), 8.85 (s, 1H)

[0117] 4-(4,5-Dimethylindan-1-yl)-1H-imidazole. M.p of hydrochloride161-164° C.

[0118]¹H NMR (as HCl-salt, MeOH-d₄) 2.06-2.18 (m, 1H), 2.22 (s, 3H),2.26 (s, 3H), 2.56-2.68 (m, 1H), 2.87-3.11 (m, 2H), 4.55 (t, 1H), 6.78(d, J=7.6 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 7.27 (s, 1H), 8.80 (s, 1H)

[0119] 4-(5,7-Dimethylindan-1-yl)-1H-imidazole

[0120]¹H NMR (CDCl₃); 2.07 (s, 3H), 2.07-2.22 (m, 1H), 2.31 (s, 3H),2.40-2.53 (m, 1H), 2.77-2.87 (m, 1H), 2.94-3.05 (m, 1H), 4.44 (m, 1H),6.55 (s, 1H), 6.80 (s, 1H), 6.94 (s, 1H), 7.53 (s, 1H)

[0121] 4-(2,4-Dimethylindan-1-yl)-1H-imidazole

[0122]¹H NMR (CDCl₃): 1.23 (d, 3H), 2.28 (s, 3H), 2.46-2.55 (m, 2H),3.05-3.16 (m, 1H), 3.92 (d, 1H), 6.81-6.83 (m, 2H), 6.95-7.09 (m, 2H),7.56 (s, 1H)

[0123] 4-(5-Methoxyindan-1-yl)-1H-imidazole. M.p. 180-184° C.

[0124]¹H NMR (CDCl₃+MeOH-d₄); 2.09-2.19 (m, 1H), 2.48-2.59 (m, 1H),2.87-2.98 (m, 2H), 3.79 (s, 3H), 4.35 (t, 1H), 6.69-6.73 (m, 2H), 6.82(d, J=2.0 Hz, 1H), 7.03 (d, J=8.2 Hz, 1H), 7.53 (s, 1H)

[0125] 4-(7-Methoxyindan-1-yl)-1H-imidazole

[0126]¹H NMR (CDCl₃); 2.20-2.50 (m, 2H), 2.83-2.98 (m, 2H), 3.82 (s,3H), 4.50-4.54 (m, 1H), 6.66-6.72 (m, 2H), 6.86 (d, J=7.7 Hz, 1H), 7.16(t, J=7.7 Hz, 1H), 7.43 (s, 1H)

EXAMPLE 2

[0127] 4-(1-Methylindan-1-yl)-1H-imidazole

[0128] a) 2-(3-Benzyl-3H-imidazol-4-yl)4-phenylbutan-2-ol

[0129] 1.0 g of magnesium turnings are covered with 5 ml of drytetrahydrofuran. To the mixture is added 7.8 g of (2-bromoethyl)benzenein 30 ml of dry tetrahydrofuran at such a rate that a smooth reaction ismaintained. The mixture is then heated under reflux for one hour. Afterbeing cooled to room temperature, 3.0 g of1-(3-benzyl-3H-imidazol-4-yl)-ethanone in 20 ml of tetrahyrofuran isadded dropwise to the Grignard reagent and the reaction mixture isrefluxed for one hour. The cooled reaction mixture is poured into a colddilute hydrochloric acid solution. Work-up of the mixture gives thecrude product, which is recrystallized from ethyl acetate. The yield is3.3 g.

[0130]¹H NMR (as HCl-salt, MeOH-d₄): 1.67 (s, 3H), 2.01-2.08 (m, 2H),2.37-2.48 (m, 1H), 2.57-2.71 (m, 1H), 5.75 (dd, 2H), 6.97-7.42 (m, 10H),7.50 (s, 1H), 8.75 (s, 1H)

[0131] b) 2-(1H-Imidazol-4-yl)4-phenylbutan-2-ol

[0132] 3.3 g of 2-(3-benzyl-3H-imidazol-4-yl)-4-phenylbutan-2-ol isdissolved in 100 ml of ethanol. The reaction solution is hydrogenated at50° C. with 10% palladium on carbon as catalyst for 4.5 hours. Work-upof the reaction mixture gives the crude product, which is recrystallizedfrom ethyl acetate. The yield is 2.0 g.

[0133]¹H NMR (MeOH-d₄): 1.56 (s, 3H), 2.01-2.13 (m, 2H), 2.37-2.47 (m,1H), 2.53-2.64 (m, 1H), 6.96 (s, 1H), 7.07-7.13 (m, 3H), 7.18-7.23 (m,2H), 7.61 (s, 1H)

[0134] c) 4-(1-Methylindan-1-yl)-1H-imidazole

[0135] A mixture of 2-(1H-imidazol-2-yl)-4-phenylbutan-2-ol (0.5 g) andmethanesulfonic acid (12 ml) is heated at 100° C. for 35 minutes. Thecooled reaction mixture is poured into water and is made alkaline withsodium hydroxide solution. The product is extracted into ethyl acetatewhich is washed with water, dried with sodium sulfate and evaporatedunder reduced pressure. The product is converted to its hydrochloridesalt in ethyl acetate using dry hydrochloric acid. The yield is 387 mg,m.p. 164-171° C.

[0136]¹H NMR (as HCl-salt, MeOH-d₄): 1.67 (s, 3H), 2.21-2.30 (m, 1H),2.40-2.50 (m, 1H), 2.96-3.11 (m, 2H), 7.06-7.33 (m, 5H), 8.84 (s, 1H)

EXAMPLE 3

[0137] 4-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-imidazole

[0138] a) 4-(2-Chlorophenyl)-1-(1H-imidazol-4-yl)-butan-1-ol

[0139] 3.3 g of magnesium turnings are covered with 40 ml of drytetrahydrofuran. To the mixture is added 32.0 g of1-(3-bromopropyl)-2-chlorobenzene (prepared according to Baddar, F. G.et al., J. Chem. Soc., 1959, 1027) in 100 ml of dry tetrahydrofuran atsuch a rate that a smooth reaction is maintained. When the magnesiumturnings have reacted the solution is cooled to room temperature. 4.3 gof imidazole-4-carbaldehyde in 40 ml of dry tetrahydrofuran is thenadded dropwise to the Grignard reagent and the reaction mixture isrefluxed for one hour. The cooled reaction mixture is poured into a colddilute hydrochloric acid solution. Tetrahydrofuran is distilled offunder reduced pressure and the residue is cooled. The resultingprecipitate is filtered and washed with water. The crude product isrecrystallized from ethanol. The yield is 8.0 g. Melting point of thehydrochloride salt is 152-154° C.

[0140]¹H NMR (as HCl-salt, MeOH-d₄): 1.65-1.91 (m, 4H), 2.80 (t, 2H),4.82, (t, 1H), 7.14-7.35 (m, 4H), 7.40 (s, 1H), 8.83 (s, 1H)

[0141] b) 4-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-imidazole

[0142] A mixture of 4-(2-chlorophenyl)-1-(1H-imidazol-4-yl)-butan-1-olhydrochloride (1.0 g) and methanesulfonic acid (15 ml) is heated at 100°C. for 2 hours. The cooled reaction mixture is poured into water and ismade alkaline with sodium hydroxide solution. The product is extractedinto ethyl acetate which is washed with water, dried with sodium sulfateand evaporated under reduced pressure. The crude product isrecrystallized from ethyl acetate. The yield is 0.4 g, m.p. 165-169° C.

[0143]¹H NMR (CDCl₃): 1.74-1.83 (m, 2H), 1.95-2.15 (m, 2H), 2.70-2.91(m, 2H), 4.19 (t, 1H), 6.49 (s, 1H), 6.96-7.05 (m, 2H), 7.21-7.24 (m,1H), 7.54 (s, 1H)

EXAMPLE 4

[0144] 4-(1,2,3,4-Tetrahydronaphthalen-1-yl)-1H-imidazole

[0145] 4-(5-Chloro-1,2,3,4-tetrahydronaphthalen-1-yl)-1H-imidazole (300mg) is dissolved in ethanol (15 ml). The reaction solution ishydrogenated at 50° C. with 10% palladium on carbon as catalyst for 8hours. The mixture is filtered to remove the catalyst, and the filtrateis evaporated under reduced pressure. The residue is dissolved in waterand is made alkaline with sodium hydroxide solution. The product isextracted into methylene chloride which is washed with water, dried withsodium sulfate and evaporated under reduced pressure. The crude productis recrystallized from ethyl acetate. The yield is 169 mg, m.p. 105-110°C.

[0146]¹H NMR (CDCl₃): 1.70-1.85 (m, 2H), 2.05-2.11 (m, 2H), 2.78-2.86(m, 2H), 4.21 (t, 1H), 6.59 (s, 1H), 7.04-7.14 (m, 4H), 7.52 (s, 1H)

EXAMPLE 5

[0147] 3-(1H-Imidazol4-yl)-5-isobutylindan-1-ol

[0148] a)3-(3-Benzyl-3H-imidazol-4-yl)-1-(4-isobutylphenyl)-propen-1-one

[0149] A solution of 4-isobutylacetophenone (2.0 g),3-benzyl-3H-imidazole-4-carbaldehyde (2.1 g) and 48% sodium hydroxide(0.65 ml) in methanol (20 ml) is heated at 55-60° C. for 6 hours. Thereaction mixture is then cooled in an ice bath. The resultingprecipitate is filtered, and rinsed with methanol. The yield is 2.5 g.

[0150]¹H NMR (CDCl₃): 0.91 (d, 6H), 1.85-1.95 (m, 1H), 2.54 (d, 2H),5.28 (s, 2H), 7.12-7.14 (m, 2H), 7.23 (d, J=8.2 Hz, 2H), 7.30-7.41 (m,4H), 7.60-7.68 (m, 3H), 7.80 (d, J=8.2 Hz, 2H)

[0151] b) 3-(3-Benzyl-3H-imidazol-4-yl)-5-isobutylindan-1-one

[0152] A mixture of3-(3-benzyl-3H-imidazol-4-yl)-1-(4-isobutylphenyl)-propen-1-one (2.4 g)and methanesulfonic acid (40 ml) is heated at 120° C. for 40 minutes.Work-up of the reaction mixture gives the crude product, which ispurified by flash chromatography by eluting with methylenechloride-methanol solution. The yield is 0.5 g.

[0153]¹H NMR (CDCl₃): 0.89 (d, 6H), 1.81-1.91 (m, 1H), 2.34 (dd, J=18.8Hz, J=4.0 Hz, 1H), 2.51 (d, 2H), 2.80 (dd, J=18.8 Hz, J=7.9 Hz, 1H),4.44-4.48 (m, 1H), 5.03-5.16 (m, 2H), 6.64 (s, 1H), 7.05-7.08 (m, 2H),7.13 (s, 1H), 7.22 (d, J=7.8 Hz, 1H), 7.26-7.39 (m, 3H), 7.57 (s, 1H),7.68 (d, J=7.8 Hz, 1H)

[0154] c) 3-(1H-Imidazol-4-yl)-5-isobutylindan-1-ol

[0155] 3-(3-Benzyl-3H-imidazol-4-yl)-5-isobutylindan-1-one (0.5 g) isdissolved in ethanol (15 ml). The reaction solution is hydrogenated at50° C. with 10% palladium on carbon as catalyst until no more hydrogenis consumed. The mixture is filtered to remove the catalyst, and thefiltrate is evaporated under reduced pressure. The crude productcontains cis- and trans-isomers. The isomers are purified by flashchromatography.

[0156]¹H NMR (cis-isomer, CDCl₃): 0.85 (d, 6H), 1.74-1.84(m, 1H),2.15-2.20 (m, 1H), 2.40 (d, 2H), 2.69-2.79 (m, 1H), 4.33 (d, 1H), 5.16(d, 1H), 6.91 (s, 1H), 6.93 (s, 1H), 7.02 (d, J=7.7 Hz, 1H), 7.39 (d,J=7.7 Hz, 1H), 7.42 (s, 1H) ¹H NMR (trans-isomer, CDCl₃): 0.85 (d, 6H),1.74-1.84 (m, 1H), 2.35-2.46 (m, 4H), 4.60 (t, 1H), 5.26 (t, ₁H), 6.65(s, 1H), 6.95 (s, 1H), 7.04 (d, J=7.7 Hz, 1H), 7.33 (d, J=7.7 Hz, 1H),7.46 (s, 1H)

EXAMPLE 6

[0157] 3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one

[0158] a)3-(3-Benzyl-3H-imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one

[0159] A mixture of 2,3-dimethylanisole (2.0 g),3-(3-benzyl-3H-imidazol-4-yl)-acrylic acid (3.4 g) and methanesulfonicacid (60 ml) is heated at 90-95° C. for 45 minutes.The cooled reactionmixture is poured into water and is made alkaline with sodium hydroxidesolution. The product is extracted into ethyl acetate which is washedwith water, dried with sodium sulfate and evaporated in reducedpressure. The crude product is purified by flash chromatography byeluting with methylene chloride-methanol solution. The yield is 1.1 g.

[0160]¹H NMR (CDCl₃): 2.13 (s, 3H), 2.35 (dd, J=18.5 Hz, J=4.1 Hz, 1H),2.61 (s, 3H), 2.81 (dd, J=18.5 Hz, J=8.2 Hz, 1H), 3.76 (s, 3H),4.34-4.38 (m, 1H), 5.05 (s, 2H), 6.52 (s, 1H), 6.72 (s, 1H), 7.00-7.05(m, 2H), 7.29-7.36 (m, 3H), 7.56 (s, 1H)

[0161] b) 3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one

[0162] 3-(3-Benzyl-3H-imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one(1.1 g) is dissolved in ethanol (90 ml). The reaction solution ishydrogenated at 50-55° C. with 10% palladium on carbon as catalyst for 7hours. The mixture is filtered to remove the catalyst, and the filtrateis evaporated under reduced pressure. The product is converted to itshydrochloride salt in ethyl acetate using dry hydrochloric acid. Theyield is 0.6 g, m.p. 258-261° C.

[0163]¹H NMR (as HCl-salt, MeOH-d₄): 2.16 (s, 3H), 2.62 (s, 3H), 2.68(dd, J=18.7 Hz, J=4.0 Hz, 1H), 3.18 (dd, J=18.7 Hz, J=8.3 Hz, 1H), 3.87(s, 3H), 4.77-4.81 (m, 1H), 6.81 (s, 1H), 7.43 (s, 1H), 8.85 (s, 1H)

[0164] Using the same method the following compound was prepared:

[0165] 3-(1H-Imidazol-4-yl)-5-methoxy-4,7-dimethylindan-1-one

[0166]¹H NMR (CDCl₃): 1.96 (s, 3H), 2.64 (dd, J=18.6 Hz, J=2.1 Hz, 1H),2.65 (s, 3H), 3.13 (dd, J=18.6 Hz, J=8.4 Hz, 1H), 3.90 (s, 3H),4.57-4.61 (m, 1H), 6.47 (s, 1H), 6.68 (s, 1H), 7.50 (s, 1H)

EXAMPLE 7

[0167] 3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-ol

[0168] 3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-one (0.53 g)is dissolved in ethanol (30 ml) and 0.3 g of sodium borohydride isadded. The mixture is stirred at 35-40° C. for 7 hours. About 20 ml ofethanol is then distilled off and 30 ml of water is added. The solutionis extracted with ethyl acetate. The combined ethyl acetate extracts arewashed with water, dried with sodium sulfate, and evaporated underreduced pressure. The product is the mixture of cis- and trans-isomers(about 85:15). Crystallization of the product from ethyl acetate gives acis-isomer, m.p. 184-189° C.

[0169]¹H NMR (cis-isomer, CDCl₃): 2.09-2.14 (m, 1H), 2.11 (s, 3H), 2.38(s, 3H), 2.69-2.77 (m, 1H), 3.73 (s, 3H), 4.31 (d, 1H), 5.26 (d, 1H),6.48 (s, 1H), 6.90 (s, 1H), 7.43 (s, 1H)

EXAMPLE 8

[0170] 4-(6-Methoxy-4,5-dimethylindan-1-yl)-1H-imidazole

[0171] 3-(1H-Imidazol-4-yl)-5-methoxy-6,7-dimethylindan-1-ol (0.29 g) isdissolved in the mixture of ethanol (30 ml) and concentratedhydrochloric acid (0.2 ml). The solution is hydrogenated at 50-55° C.with 10% palladium on carbon as catalyst until no more hydrogen isconsumed, The mixture is filtered and the filtrate is evaporated todryness. The residue is crystallized from the mixture of ethyl acetateand ethanol. M.p. of the hydrochloride salt is 174-177° C.

[0172]¹H NMR (as HCl-salt, MeOH-d₄): 2.05-2.17 (m, 1H), 2.11 (s, 3H),2.21 (s, 3H), 2.54-2.66 (m, 1H), 2.82-3.05 (m, 2H), 3.71 (s, 3H), 4.55(t, 1H), 6.50 (s, 1H), 7.27 (s, 1H), 8.79 (s, 1H)

[0173] Using the same method the following compound was prepared:

[0174] 4-(6-Isobutylindan-1-yl)-1H-imidazole

[0175]¹H NMR (as HCl-salt, MeOH-d₄): 0.86 (d, 6H), 1.73-1.83 (m, 1H),2.11-2.18 (m, 1H), 2.42 (d, 2H), 2.58-2.65 (m, 1H), 2.97-3.31 (m, 2H),4.56 (t, 1H), 6.85 (s, 1H), 7.04 (d, J=7.6 Hz, 1H), 7.22 (d, J=7.6 Hz,1H), 7.30 (s, 1H), 8.83 (s, 1H)

EXAMPLE 9

[0176] 3-(1H-imidazol-4-yl)-6,7-dimethylindan-5-ol

[0177] A stirred mixture of4-(6-methoxy-4,5-dimethylindan-1-yl)-1H-imidazole hydrochloride (0.29 g)and hydrobromic acid (15 ml) is heated under reflux for 40 minutes. Thecooled reaction mixture is poured into water and is made basic withammonium hydroxide solution. The product is extracted into ethyl acetatewhich is washed with water, dried with sodium sulfate and evaporated todryness. The crude product is purified by flash chromatography andcrystallized from ethyl acetate. M.p. 198-202° C.

[0178]¹H NMR (CDCl₃+MeOH-d₄): 2.02-2.13 (m, 1H), 2.13 (s, 3H), 2.18 (s,3H), 2.43-2.54 (m, 1H), 2.71-2.82 (m, 1H), 2.86-2.96 (m, 1H), 4.33 (t,1H), 6.49 (s, 1H), 6.75 (s, 1H), 7.50 (s, 1H)

[0179] Using the same method the following compound was prepared:

[0180] 5-Hydroxy-3-(1H-imidazol-4-yl)-6,7-dimethylindan-1-one

[0181]¹H NMR (MeOH-d₄): 2.12 (s, 3H), 2.58 (s, 3H), 2.67 (dd, J=18.4 Hz,J=4.1 Hz, 1H), 3.02 (dd, J=18.4 Hz, J=8.0 Hz, 1H), 4.43-4.47 (m, 1H),6.59 (s, 1H), 6.90 (s, 1H), 7.62 (s, 1H)

[0182] 1-(1H-Imidazol-4-yl)-indan5-ol. M.p. 210-220° C.

[0183]¹H NMR(MeOH-d₄): 2.04-2.17 (m, 1H), 2.41-2.52(m, 1H), 2.77-2.97(m, 2H), 4.27 (t, 1H), 6.55 (dd, J=8.1 Hz, J=2.3 Hz, 1H), 6.67 (d, J=2.3Hz, 1H), 6.70 (s, 1H), 6.84 (d, J=8.1 Hz, 1H), 7.57 (s, 1H)

[0184] 3-(1H-imidazol-4-yl)-indan-4-ol. M.p. 142-145° C.

[0185]¹H NMR (CDCl₃+MeOH-d₄): 2.13-2.26 (m, 1H), 2.49-2.60 (m, 1H).2.89-3.08 (m, 2H), 4.54 (t, 1H), 6.71-6.76 (m, 3H), 7.06 (t, J=7.6 Hz,1H), 7.55 (s, 1H)

EXAMPLE 10

[0186] 4-(3-Ethoxy-6-methoxy4,5-dimethylindan-1-yl)- 1H-imidazole(cis-isomer)

[0187] 3-(1H-Imidazol4-yl)-5-methoxy-6,7-dimethylindan-1-ol (cis-isomer,0.1 g) is dissolved in the mixture of ethanol (20 ml) and concentratedhydrochloric acid (2 ml). The solution is stirred at 25° C. for onehour. Work-up of the reaction mixture gives the crude product, which ispurified by flash chromatography using methylene chloride-methanol aseluent.

[0188]¹H NMR (CDCl₃): 1.31 (t, J=7.0 Hz, 3H), 2.12 (s, 3H), 2.20-2.25(m, 1H), 2.32 (s, 3H), 2.51-2.60 (m, 1H), 3.72 (q, J=7.0 Hz, 2H), 3.73(s, 3H), 4.40 (d, 1H), 4.96 (d, 1H), 6.52 (s, 1H), 6.93 (s, 1H), 7.41(s, 1H)

EXAMPLE 11

[0189] 4-(Indan-1-yl)-1H-imidazole

[0190] a) 4-(3H-Inden-1-yl)-1H-imidazole

[0191] To a stirred solution of 1-(N,N-dimethylsulfamoyl)-1H-imidazole(1.9 g, prepared according to Chadwick, D. J. and Ngochindo, R. I., J.Chem. Soc., Perkin Trans. (1984, 481) in dry tetrahydrofuran (90 ml) at−70° C. under nitrogen, is added dropwise 2.5 M butyllithium in hexane(5.1 ml). After 30 minutes tert-butyldimethylsilyl chloride (2.0 g) indry tetrahydrofuran (5 ml) is added and the mixture is allowed to warmto 25° C. After 1.5 hours the mixture is again cooled to −70° C. andtreated with 2.5 M butyllithium in hexane (5.3 ml). After 30 minutes,1-indanone (2.1 g) in dry tetrahydrofuran (5 ml) is added and themixture is allowed to warm to room temperature. The reaction mixture isthen quenched with saturated Na₂CO₃ solution (2 ml), and the solvent isremoved under reduced pressure. The residue is dissolved in methylenechloride and washed with water, dried with sodium sufate and evaporatedto dryness under reduced pressure. The bis-protected intermediate isrefluxed with 2 N hydrochloric acid (200 ml) for 2 hours. The cooledsolution is made basic by ammonium hydroxide solution, and extractedwith methylene chloride. The organic layer is washed with water, driedwith sodium sulfate and the solvent removed under reduced pressure. Thecrude product is purified by flash chromatography using methylenechloride-methanol as eluent. The product is converted to thehydrochloride salt in ethyl acetate-ethanol solution, m.p. 232-240° C.

[0192]¹H NMR (as HCl-salt, MeOH-d₄); 3.66 (d, 2H), 7.07 (t, 1H),7.31-7.43 (m, 2H), 7.59 (d, 1H), 7.68 (d, 1H), 8.03 (s, 1H), 9.06 (s,1H)

[0193] b) 4-(Indan-1-yl)-1H-imidazole

[0194] 4-(3H-Inden-1-yl)-1H-imidazole hydrochloride (80 mg) is dissolvedin ethanol (6 ml). The reaction solution is hydrogenated at 40-50° C.with 10% palladium on carbon as catalyst until no more hydrogen isconsumed. Work-up of the reaction mixture gives the crude product whichis purified by flash chromatography using methylene chloride-methanol aseluent.

[0195]¹H NMR (CDCl₃): 2.08-2.19 (m, 1H), 2.41-2.51 (m, 1H), 2.80-2.95(m, 2H), 4.37 (t, 1H), 6.65 (s, 1H), 7.07-7.21 (m, 4H), 7.25 (s, 1H)

[0196] Using the same method the following compound was prepared:

[0197] 4-(6-Methoxyindan-1-yl)-1H-imidazole

[0198]¹H NMR (as HCl-salt, MeOH-d₄); 2.08-2.20 (m, 1H), 2.56-2.67 (m,1H), 2.80-2.97 (m, 2H), 3.72 (s, 3H), 4.53 (t, 1H), 6.71 (d, J=1.9 Hz,1H), 6.75 (dd, J=8.3 Hz, J=1.9 Hz, 1H), 6.92 (s, 1H), 7.15 (d, J=83 Hz,1H), 8.82 (s, 1H)

EXAMPLE 12

[0199] 4-(Indan-1-ylmethyl)-1H-imidazole

[0200] Titanium tetrachloride (17.2 g) is added dropwise to a stirredsuspension of zinc powder (11.9 g) in tetrahydrofuran (100 ml) with icecooling under a nitrogen atmosphere. The mixture is heated at reflux forone hour. After being cooled to room temperature, 1-indanone (2.0 g) and3-benzyl-3H-imidazole-4-carbaldehyde (4.2 g) in tetrahydrofuran (30 ml)are added into the mixture. The mixture is refluxed with stirring for 3hours. The cooled reaction mixture is made alkaline with dilute sodiumhydroxide solution. The slurry is filtered, and the filtratate isevaporated to dryness under reduced pressure. The residue, whichcontains the crude intermediate1-benzyl-5-(indan-1-ylidenemethyl)-1H-imidazole is purified by flashchromatography.

[0201] The purified intermediate (0.8 g) is dissolved in the mixture ofethanol (30 ml), water (2 ml) and concentrated hydrochloric acid (0.5ml). The reaction mixture is hydrogenated at 50-60° C. with 10%palladium on carbon as catalyst until no more hydrogen is consumed. Themixture is filtered, and the filtrate is evaporated to dryness. Theresidue is dissolved in water and is made alkaline with sodiumhydroxide. The product is then extracted into methylene chloride whichis washed with water, dried with sodium sulfate and evaporated todryness. The product is converted to its hydrochloride salt in ethylacetate using dry hydrochloric acid. The yield is 0.5 g, m.p. 182-183°C.

[0202]¹H NMR (as HCl-salt, MeOH-d₄): 1.74-1.81 (m, 1H), 2.22-2.29 (m,1H), 2.80-2.95 (m, 3H), 3.17 (dd, J=15.1 Hz, J=5.7 Hz, 1H), 3.48-3.53(m, 1H), 7.12-7.23 (m, 4H), 7.26 (s, 1H), 8.79 (s, 1H).

[0203] Using the same method the following compounds were prepared:

[0204] 4-(6-Methoxyindan-1-ylmethyl)-1H-imidazole. M.p. of hydrochloride197-200° C.

[0205]¹H NMR (as HCl-salt, MeOH-d₄): 1.72-1.84 (m, 1H), 2.19-2.31 (m,1H), 2.70-2.89 (m, 3H), 3.16 (dd, J=14.9 Hz, J=5.5 Hz, 1H), 3.42-3.51(m, 1H), 3.74 (s, 3H), 6.68 (d, J=2.2 Hz, 1H), 6.74 (dd, J=8.2 Hz, J=2.2Hz, 1H), 7.10 (d, J=8.2 Hz, 1H), 7.27 (s, 1H), 8.82 (s, 1H)

[0206] 4-(5-Methoxyindan-1-ylmethyl)-1H-imidazole. M.p. of hydrochloride204-206° C.

[0207]¹H NMR (as HCl-salt, MeOH-d₄): 1.71-1.83 (m, 1H), 2.19-2.31 (m,1H), 2.75-2.94 (m, 3H), 3.13 (dd, J=15.0 Hz, J=5.5 Hz, 1H), 3.40-3.49(m, 1H), 3.75 (s, 3H), 6.70 (dd, J=8.3 Hz, J=2.2 Hz, 1H), 6.78 (d, J=2.2Hz, 1H), 7.00 (d, J=8.3 Hz, 1H), 7.26 (s, 1H), 8.82 (s, 1H)

[0208] 4-(5,6-Dimethoxyindan-1-ylmethyl)-1H-imidazole. M.p. ofhydrochloride 193-197° C.

[0209]¹H NMR (as HCl-salt, MeOH-d₄): 1.72-1.84 (m, 1H), 2.20-2.32 (m,1H), 2.75-2.88 (m, 3H), 3.15 (dd, J=15.1 Hz, J=5.2 Hz, 1H), 3.41-3.50(m, 1H), 3.77 (s, 3H), 3.79 (s, 3H), 6.73 (s, 1H), 6.84 (s, 1H), 7.26(s, 1H), 8.82 (s, 1H)

[0210] 4-(6-Methoxy-4,5-dimethylindan-1-ylmethyl)-1H-imidazole. M.p. ofhydrochloride 194-197° C.

[0211]¹H NMR (as HCl-salt, MeOH-d₄): 1.70-1.81 (m, 1H), 2.09 (s, 3H),2.15 (s, 3H), 2.17-2.29 (m, 1H), 2.69-2.89 (m, 3H), 3.14 (dd, J=15.1 Hz,J=5.7 Hz, 1H), 3.42-3.50 (m, 1H), 3.74 (s, 3H), 6.54 (s, 1H), 7.24 (s,1H), 8.81 (s, 1H)

[0212] 4-(6-Methoxy-4,7-dimethylindan-1-ylmethyl)-1H-imidazole. M.p. ofhydrochloride 168-175° C.

[0213]¹H NMR (as HCl-salt, MeOH-d₄); 1.88-1.94 (m, 1H), 2.07 (s, 3H),2.09-2.18 (m, 1H), 2.19 (s, 3H), 2.69-2.77 (m, 3H), 2.90 (dd, J=15.2 Hz,J=4.7 Hz, 1H), 3.51-3.57 (m, 1H), 3.77 (s, 3H), 6.60 (s, 1H), 7.21 (s,1H), 8.80 (s, 1H)

[0214] 4-(6-Methoxy-5-methylindan-1-ylmethyl)-1H-imidazole. M.p. ofhydrochloride 183-186° C.

[0215]¹H NMR (as HCl-salt, MeOH-d₄): 1.71-1.82 (m, 1H), 2.13 (s, 3H),2.18-2.29 (m, 1H), 2.70-2.89 (m, 3H), 3.16 (dd, J=15.0 Hz, J=5.4 Hz,1H), 3.42-3.50 (m, 1H), 3.76 (s, 3H), 6.65 (s, 1H), 6.95 (s, 1H), (s,1H), 8.82 (s, 1H)

[0216] 4-(6-Fluoroindan-1-ylmethyl)-1H-imidazole. M.p. of hydrochloride215-222° C.

[0217]¹H NMR (as HCl-salt, MeOH-d₄): 1.76-1.88 (m, 1H), 2.23-2.35 (m,1H), 2.76-2.92 (m, 3H), 3.18 (dd, J=15.3 Hz, J=5.3 Hz, 1H), 3.46-3.56(m, 1H), 6.86-6.92 (m, 2H), 7.17-7.20 (m, 1H), 7.31 (s, 1H), 8.83 (s,1H)

[0218] 4-(5-Fluoroindan-1-ylmethy)-1H-imidazole. M.p. of hydrochloride185-189° C.

[0219]¹H NMR (as HCl-salt, MeOH-d₄): 1.76-1.88 (m, 1H), 2.23-2.35 (m,1H), 2.79-2.98 (m, 3H), 3.16 (dd, J=15.3 Hz, J=5.3 Hz, 1H), 3.43-3.53(m, 1H), 6.83-6.96 (m, 2H), 7.08-7.13 (m, 1H), 7.29 (s, 1H), 8.82 (s,1H)

[0220] 4-(4-Methoxyindan-1-ylmethyl)-1H-imidazole. M.p. of hydrochloride202-210° C.

[0221]¹H-NMR (as HCl-salt, MeOH-d₄): 1.73-1.82 (m, 1H), 2.18-2.30 (m,1H), 2.72-289 (m, 3H), 3.14 (dd, J=15.0 Hz, J=5.5 Hz, 1H), 3.48-3.56 (m,1H), 3.80 (s, 3H), 6.72-6.78 (m, 2H), 7.14 (t, 1H), 7.24 (s, 1H), 8.79(s, 1H)

[0222] 4-(6-Methoxy-7-methylindan-1-ylmethyl)-1H-imidazole. M.p. ofhydrochloride 152-158° C.

[0223]¹NMR (as HCl-salt, MeOH-d₄): 1.86-1.93 (m, 1H), 2.11 (s, 3H),2.12-2.20 (m, 1H), 2.68-2.96 (m, 4H), 3.52-3.59 (m, 1H), 3.79 (s, 3H),6.75 (d, J=8.2 Hz, 1H), 6.99 (d, J=8.2 Hz, 1H), 7.22 (s, 1H), 8.79 (s,1H)

EXAMPLE 13

[0224] 4-[1-(Indan-1-yl)-ethyl]-1H-imidazole

[0225] The procedure of Example 12 is repeated except that1-(3-benzyl-3H-imidazol-4-yl)-ethanone is used in place of3-benzyl-3H-imidazole-4-carbaldehyde. The product contains twodiastereomers ad and bc (78% of ad and 22% of bc).

[0226]¹H NMR (as HCl-salt, MeOH-d₄): 1.23 (d, J=7.1 Hz, —CH₃, bcdiastereomer), 1.38 (d, J=7.1 Hz, —CH₃, ad diastereomer), 1.81-2.32 (m,2H), 2.70-2.87 (m, 2H), 3.29-3.39 (m, 1H), 3.47-3.57 (m, 1H), 6.98-7.30(m, 5H), 8.77 (s, 1H, ad (diastereomer), 8.84 (s, 1H, bc diastereomer)

[0227] Using the same method the following substituted derivative wasprepared:

[0228] 4-[1-(6-Methoxyindan-1-yl)-ethyl]-1H-imidazole

[0229] The reaction mixture contains two diastereomers ad and bc, whichare separated by flash chromatography eluting with methylenechloride-methanol solution.

[0230]¹H NMR (ad diastereomer as HCl-salt, MeOH-d₄): 1.37 (d, J=7.1 Hz,3H), 1.83-1.94 (m, 1H), 2.20-2.33 (m, 1H), 2.58-2.77 (m, 2H), 3.30-3.39(m, 1H), 3.43-3.49 (m, 1H), 3.74 (s, 3H), 6.63 (d, J=2.4 Hz, 1H), 6.73(dd, J=8.2 Hz, J=2.4 Hz, 1H), 7.05 (d, J=8.2 Hz, 1H), 7.13 (s, 1H), 8.74(s, 1H)

[0231]¹H NMR (bc diastereomer as HCl-salt, MeOH-d₄): 1.23 (d, J=7.1 Hz,3H), 1.90-2.01 (m, 1H), 2.05-2.16 (m, 1H), 2.70-81 (m, 2H), 3.29-3.39(m, 1H), 3.43-3.54 (m, 1H), 3.72 (s, 3H), 6.54 (d, J=2.4 Hz, 1H) 6.73(dd, J=8.2 Hz, J2.4 Hz, 1H) 7.11 (d, J=8.2 Hz, 1H), 7.32 (s, 1H), 8.84(s, 1H)

EXAMPLE 14

[0232] 4-(5-tert-Butyl-6-methoxyindan-1-ylmethyl)-1H-imidazole

[0233] Sulfuric acid (0.5 ml) is added into the mixture of4-(6-methoxyindan-1-ylmethyl)-1H-imidazole hydrochloride (50 mg) andtert-butanol (2 ml). The mixture is stirred at 35-40° C. for 10 hours.The reaction mixture is then poured into water and is made alkaline withsodium hydroxide. The product is extracted into methylene chloride whichis washed with water, dried with sodium sulfate and evaporated todryness. The residue consisting of crude product is converted to itshydrochloride salt in ethyl acetate. The yield is 23 mg, m.p. 174-184°C.

[0234]¹H NMR (as HCl-salt, MeOH-d₄): 1.33 (s, 9H), 1.71-1.83 (m, 1H),2.19-2.31 (m, 1H), 2.73-2.89 (m, 3H), 3.15 (dd, J=15.0 Hz, J=5.1 Hz,1H), 3.40-3.50 (m. 1H), 3.77 (s, 3 H), 6.69 (s, 1H), 7.11 (s, 1H), 7.27(s, 1H), 8.81 (s, 1H)

[0235] Using the same method the following compound was prepared:

[0236] 4-(6-tert-Butyl-5-methoxyindan-1-ylmethyl)-1H-imidazole

[0237]¹H NMR (as HCl-salt, MeOH-d₄): 1.30 (s, 9H), 1.73-1.84 (m, 1H),2.21-2.33 (m, 1H), 2.75-2.94 (m, 3H), 3.05 (dd, J=14.9 Hz, J=6.3 Hz,1H), 3.35-3.45 (m, 1H), 3.80 (s, 3H), 6.83 (s, 1H), 6.86 (s, 1H), 7.23(s, 1H), 8.81 (s, 1H)

[0238] 5,7-Di-tert-butyl-1-(1H-imidazol-4-ylmethyl)-indan-4-ol

[0239]¹H NMR (as HCl-salt, MeOH-d₄): 1.39 (s, 9H), 1.41 (s, 9H),1.87-1.93 (m, 1H), 2.01-2.06 (m, 1H), 2.66-2.75 (m, 3H), 2.89-2.95 (m,1H), 3.82-3.89 (m, 1H), 7.15 (s, 1H), 7.33 (s, 1H), 8.77 (s, 1H)

[0240] 6-tert-Butyl-1-(1H-imidazol-4-yl)-indan-5-ol

[0241]¹H NMR (as HCl-salt, MeOH-d₄): 1.32 (s, 9H), 2.06-2.15 (m, 1H),2.52-2.63 (m, 1H), 2.82-3.02 (m, 2H), 4.46 (t, ₁H), 6.69 (s, 1H), 6.88(s, 1H), 7.25 (s, 1H), 8.79 (s, 1H)

[0242] 4-(6-tert-Butyl-4-methylindan-1-yl)-1H-imidazole. M.p. ofhydrochloride 235-242° C.

[0243]¹H NMR (as HCL-salt, MeOH-d₄): 1.25 (s, 9H), 2.09-2.19 (m, 1H),2.57-2.67 (m, 1H), 2.84-3.07 (m, 2H), 4.55 (t, 1H), 6.91 (s, 1H), 7.12(s, 1H), 7.25 (s, 1H), 8.74 (s, 1H)

[0244] 5,7-Di-tert-Butyl-3-(1H-imidazol-4-yl)-indan-4-ol. M.p. ofhydrochloride 216-222° C.

[0245]¹H NMR (as HCl-salt, MeOH-d₄): 1.35 (s, 9H), 1.39 (s, 9H),2.11-2.18 (m, 1H), 2.44-2.52 (m, 1H), 3.06-3.16 (m, 2H), 459-4.63 (m,1H), 6.78 (s, 1H), 7.23 (s, 1H), 8.75 (s, 1H)

EXAMPLE 15

[0246] 3-(1H-Imidazol-4-ylmethyl)-indan-5-ol

[0247] A stirred mixture of 4-(6-methoxyindan-1-ylmethyl)-1H-imidazolehydrochloride (140 mg) and 48% hydrobromic acid (7 ml) is heated underreflux for 45 minutes. The cooled reaction mixture is poured into waterand is made basic with ammonium hydroxide solution. The product isextracted into ethyl acetate which is washed with water, dried withsodium sulfate and evaporated to dryness. The crude product is covertedto its hydrochloride salt in ethyl acetate. M.p. 206-208° C.

[0248]¹H NMR (as HCl-salt, MeOH-d₄): 1.70-1.81 (m, 1H), 2.18-2.29 (m,1H), 2.70-2.88 (m, 3H), 3.12 (dd, J=5.3 Hz, J=5.8 Hz, 1H), 3.38-3.46 (m,1H), 6.53 (d, J=2.2 Hz, 1H), 6.60 (dd, J=8.1 Hz, J=2.2 Hz, 1H), 7.01 (d,J=8.1 Hz, 1H), 7.27 (s, 1H), 8.81 (s, 1H)

[0249] Using the same method the following compounds were prepared:

[0250] 1-(1H-Imidazol-4ylmethyl)-indan-5-ol. M.p. of hydrochloride159-161° C.

[0251]¹H NMR (as HCl-salt, MeOH-d₄); 1.69-1.80 (m, 1H), 2.17-2.29 (m,1H), 2.71-2.89 (m, 3H), 3.11 (dd, J=14.8 Hz, J=5.7 Hz, 1H), 3.35-3.45(m, 1H), 6.57 (dd, J=8.1 Hz, J=2.2 Hz, 1H), 6.64 (d, J=2.2 Hz, 1H), 6.89(d, J=8.1 Hz, 1H), 7.24 (s, 1H), 8.79 (s, 1H)

[0252] 1(1H-imidazol-4-dimethyl)-indan-5,6-diol

[0253]¹H NMR (as HCl-salt, MeOH-d₄): 1.67-1.78 (m, 1H), 2.15-2.27 (m,1H), 2.65-2.85 (m, 3H), 3.05 (dd, J=15.1 Hz, J=5.8 Hz, 1H), 3.30-3.40(m, 1H), 6.51 (s, 1H), 6.63 (s, 1H), 7.24 (s, 1H), 8.80 (s, 1H)

[0254] 6-tert-Butyl-3-(1H-imidazol-4-ylmethyl)-indan-5-ol

[0255]¹H NMR (as HCl-salt, MeOH-d₄): 1.35 (s, 9H), 1.69-1.79 (m, 1H),2.18-2.28 (m, 1H), 2.69-2.86 (m, 3H), 3.08 (dd, J=15.0 Hz, J=6.0 Hz,1H), 3.35-3.43 (m, 1H), 6.46 (s, 1H), 7.04 (s, 1H), 7.26 (s, 1H), 8.81(s, 1H)

[0256] 6-tert-Butyl-1-(1H-imidazol)-4-ylmethyl)-indan-5-ol. M.p. ofhydrochloride 229-230° C.

[0257]¹H NMR (as HCl-salt, MeOH-d₄): 1.32 (s, 9H), 1.72-1.81 (m, 1H),2.18-2.29 (m, 1H), 2.72-2.87 (m, 3H), 3.03 (dd, J=15.1 Hz, J=6.5 Hz,1H), 3.32-3.40 (m, 1H), 6.59 (s, 1H), 6.79 (s, 1H), 7.23 (s, 1H), 8.81(s, 1H)

[0258] 3-(1H-Imidazol-4-ylmethyl)-6,7-dimethylindan-5-ol. M.p. ofhydrochloride 229-238° C.

[0259] H NMR (as HCl-salt, MeOH-d₄): 1.66-1.78 (m, 1H), 2.08 (s, 3H),2.13 (s, 3H), 2.14-2.26 (m, 1H), 2.66-2.85 (m, 3H), 3.06 (dd, J=15.1 Hz,J=5.8 Hz, 1H), 3.35-3.43 (m, 1H), 6.39 (s, 1H), 7.22 (s, 1H), 8.79 (s,1H)

[0260] 3-(1H-imidazol-4-ylmethyl)-4,7-dimethylindan-5-ol

[0261]¹H NMR (as HCl-salt, MeOH-d₄): 1.85-1.93 (m, 1H), 2.07 (s, 3H),2.11 (s, 3H), 2.11-2.20 (m, 1H), 2.65-2.77 (m, 3H), 2.90 (dd, J=15.1 Hz,J=4.6 Hz, 1H), 3.49-3.57 (m, 1H), 6.47 (s, 1H), 7.19 (s, 1H), 8.79 (s,1H)

[0262] 3-[1-(1H-Imidazol-4-yl)-ethyl]-indan-5-ol (mixture of twodiastereomers ad and bc)

[0263]¹H NMR (base, CDCl₃+MeOH-d₄): 1.12 (d, J=7.0 Hz, —CH₃, addiastereomer), 1.22 (d, J=7.1 Hz, —CH₃, bc diastereomer)

[0264] 3-(1H-Imidazol-4-ylmethyl)-6-methylindan-5-ol

[0265]¹H NMR (as HCl-salt, MeOH-d₄): 1.68-1.79 (m, 1H), 2.13 (s, 3H),2.15-2.27 (m, 1H), 2.68-2.86 (m, 3H), 3.08 (dd, J=15.3 Hz, J=5.8 Hz,1H), 3.36-3.43 (m, 1H), 6.49 (s, 1H), 6.90 (s, 1H), 7.25 (s, 1H), 8.81(s, 1H)

[0266] 1-(1H-imidazol-4-ylmethyl)-indan4-ol. M.p. 199-205° C.

[0267]¹H NMR (MeOH-d₄): 1.68-1.80 (m, 1H), 2.10-2.22 (m, 1H), 2.60-2.86(m, 3H), 3.00 (dd, J=14.6 Hz, J=5.3 Hz, 1H), 3.38-3.48 (m, 1H), 6.56 (d,J=7.8 Hz, 1H), 6.62 (d, J=7.8 Hz, 1H), 6.71 (s, 1H), 6.94 (t, J=7.8 Hz,1H), 7.56 (s, 1H)

EXAMPLE 16

[0268] 4-(1,2,3,4-Tetrahydronaphthalen-1-ylmethyl)-1H-imidazole

[0269] The procedure of Example 12 is repeated except that 1-tetraloneis used in place of 1-indanone. The melting point of the hydrochloridesalt is 185-188° C.

[0270]¹H NMR (as HCl-salt, MeOH-d₄): 1.59-1.93 (m, 4H), 2.70-2.80 (m,2H), 2.96 (dd, J=14.8 Hz, J=9.5 Hz, 1H), 3.08-3.22 (m, 2H), 7.08-7.14(m, 4H), 7.25 (s, 1H), 8.81 (s, 1H)

[0271] Using the same method the following compounds were prepared:

[0272]4-(5-Methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole. M.p.of hydrochloride 210-218° C.

[0273]¹H NMR (as HCl-salt, MeOH-d₄): 1.58-1.64 (m, 1H), 1.71-1.86 (m,3H), 2.50-2.60 (m, 1H), 2.66-2.74 (m, 1H), 2.96 (dd, J=14.8 Hz, J=9.5Hz, 1H), 3.05-3.18 (m, 2H), 3.79 (s, 3H), 6.73-6.77 (m, 2H), 7.09 (t,1H), 7.25 (s, 1H), 8.81 (s, 1H)

[0274]4-(6-Methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole M.p.of hydrochloride 184-191° C.

[0275]¹H NMR (as HCl-salt, MeOH-d₄): 1.58-1.88 (m, 4H), 2.70-2.76(m,2H), 2.93 (dd, J=14.5 Hz, J=9.2 Hz, 1H), 3.04-3.32 (m, 2H), 3.74 (s,3H), 6.63 (d, J=2.5 Hz, 1H), 6.69 (dd, 8.4 Hz, J=2.5 Hz, 1H), 7.03 (d,J=8.4 Hz, 1H), 7.24 (s, 1H), 8.81 (s, 1H)

[0276]4-(7-Methoxy-1,2,3,4-tetrahydronaphthlalen-1-ylmethyl)-1H-imidazole.M.p. of hydrochloride 180-183° C.

[0277]¹H NMR (as base, CDCl₃) 1.59-1.82 (m, 4H), 2.64-2.68 (m, 2H), 2.85(dd, J=14.6 Hz, J=9.3 Hz, 1H), 3.01 (dd, J=14.6 Hz, J=4.8 Hz, 1H),3.12-3.17 (m, 1H), 3.72 (s, 3H), 6.68-6.71 (m, 2H), 6.78 (s, 1H),6.97-7.00 (m, 1H), 7.56 (s, 1H)

[0278] 4-(4-Methyl-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazoleThe product is the mixture of two isomers ad and bc (85% ad and 15% bc).

[0279]¹H NMR (as HCl-salt, MeOH-d₄): 1.25 (d, J=7.0 Hz, —CH₃, bcisomer), 1.30 (d, J=7.0 Hz, —CH₃, ad isomer), 1.50-2.10 (m, 4H),2.80-3.04 (m, 2H), 3.10-3.20 (m, 2H), 7.10-7.26 (m, 5H), 8.83 (s, 1H)

EXAMPLE 17

[0280]4-(7-tert-Butyl-6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole

[0281] Sulfuric acid (0.75 ml) is added into the mixture of4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazolehydrochloride (75 mg) and tert-butanol (3 ml). The mixture is stirred at35-40° C. for 15 hours. The reaction mixture is poured into water and ismade alkaline with sodium hydroxide. The product is extracted intomethylene chloride which is washed with water, dried with sodium sulfateand evaporated to dryness. The residue consisting of crude product iscoverted to its hydrochloride salt in ethyl acetate. The yield is 40 mg.

[0282]¹H NMR (as HCl-salt, MeOH-d₄): 1.28 (s, 9H), 1.65-1.95 (m, 4H),2.70-2.80 (m, 2H), 2.87-3.10 (m, 3H), 3.78 (s, 3H), 6.63 (s, 1H), 6.79(s, 1H), 7.22 (s, 1H); 8.81 (s, 1H)

EXAMPLE 18

[0283] 5-(1H-Imidazol-4-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-ol

[0284] A stirred mixture of4-(6-methoxy-1,2,3,4-tetrahydronaphthalen-1-ylmethyl)-1H-imidazole (220mg) and 48% hydrobromic acid (11 ml) is heated under reflux for onehour. The cooled reaction mixture is poured into water and is made basicwith ammonium hydroxide solution. The product is extracted into ethylacetate which is washed with water, dried with sodium sulfate andevaporated to dryness. The crude product is converted to itshydrochloride salt in ethyl acetate. The yield is 130 mg, m.p. 200-205°C.

[0285]¹H NMR (as HCl-salt, MeOH-d₄): 1.54-1.90 (m, 4H), 2.62-2.72 (m,2H), 2.88-3.11 (m, 3H), 6.51 (d, J=2.5 Hz, 1), 6.56 (dd, J=8.3 Hz, J=2.5Hz, 1H), 6.94 (d, J=8.3 Hz, 1H), 7.23 (s, 1H), 8.81 (s, 1H)

[0286] Using the same method the following compound was prepared:

[0287] 8-(1H-Imidazol-4-ylmethyl)-5,6,7,8-tetrahydronaphthalen-2-ol.M.p. of hydrochloride 245-251° C.

[0288]¹H NMR (as HCl-salt. MeOH-d₄): 1.53-1.89 (m, 4H), 2.60-2.70 (m,2H), 2.90-2.99 (m, 1H), 3.05-3.12 (m, 2H), 6.55-6.60 (m, 2H), 6.90 (d,J=8.0 Hz, 1H), 7.24 (s, 1H), 8.80 (s, 1H)

1. An imidazole derivative which is a compound of formula I

n is 0 or 1 R₁is hydrogen or C₁-C₄-alkyl R₂ is hydrogen or R₂ and R₃together form a double bond R₃ is hydrogen or C₁-C₄-alkyl or R₂ and R₃together form a double bond R₄ is hydrogen, C₁-C₄-alkyl, hydroxy orC₁C₄-alkoxy R₅ is hydrogen or C₁-C₄-alkyl or R₄ and R₅ together with thecarbon atom to which they are attached form a carbonyl group R₆, R₇ andR₈ are each the same or different and are independently hydrogen,C₁-C₄-alkyl or C₂-C₄-alkenyl, C₃-C₇-cycloalkyl, hydroxy, C₁-C₄-alkoxy,C₁-C₄-hydroxyalkyl, thiol C₁₋₄-alkylthio, C₁₋₄-alkylthiol, halogen,trifluoromethyl, nitro or optionally substituted amino X is—CHR₉—(CHR₁₀)_(m)— m is 0 or 1 and R₉ and R₁₀ are each the same ordifferent and are independently hydrogen or C₁-C₄-alkyl; or apharmaceutically acceptable ester or salt thereof.
 2. A derivativeaccording to claim 1, wherein n=m=0.
 3. A derivative according to claim1 or 2, wherein R₆, R₇ and R₈ are each hydrogen.
 4. A derivativeaccording to claim 1 or 2, wherein R₆ is lower alkyl at the position 4or 6 of the indane ring and R₇ and R₈ are hydrogen.
 5. A derivativeaccording to claim 1 or 2, wherein R₆ is lower alkoxy at the position 7of the indane ring and R₇ and, R₈ are hydrogen.
 6. A derivativeaccording to claim 1, wherein n=0 and m=1 and R₃ to R₁₀ are allhydrogen.
 7. A derivative according to claim 1, wherein n=1 and m=0. 8.A derivative according to claim 7, wherein R₁ is methyl.
 9. A derivativeaccording to claim 7 or 8, wherein R₆, R₇ and R₈ are each hydrogen. 10.A derivative according to claim 7 or 8, wherein R₆ is hydroxy at theposition 4 or 6 of the indane ring and R₇ and R₈ are hydrogen.
 11. Aderivative according to claim 7 or 8, wherein R₆ is hydroxy at theposition 5 of the indane ring and R₇ is hydroxy or lower alkyl at theposition 6 of the indane ring and R₈ is hydrogen.
 12. A derivativeaccording to claim 1, wherein n=m=1.
 13. A derivative according to claim12, wherein R₅ to R₈ are all hydrogen.
 14. A derivative according toclaim 12, wherein R₆ is a hydroxy group at the position 7 of the1,2,3,4-tetrahydronaphthyl ring and R₇ and R₈ are hydrogen.
 15. Use of aderivative as defined in any one of claims 1 to 14 as a medicament. 16.A pharmaceutically acceptable composition comprising a derivative asdefined in any one of claims 1 to 14 and a pharmaceutically acceptablecarrier.
 17. A derivative as defined in any one of claims 1 to 14, foruse in a method of treatment of the human or animal body.
 18. Aderivative as defined in any one of claims 1 to 14, for use in thetreatment of hypertension, glaucoma, chronic and acute pain, migraine,diarrhea, common cold, ischemia, addiction to chemical substances,anxiety, especially preoperative anxiety and different neurological,musculoskeletal, psychiatric and cognition disorders or as an adjunct toanesthesia.
 19. Use of a derivative as defined in any of the claims 1 to14 in the manufacture of a medicament for use in the treatment ofhypertension, glaucoma, chronic and acute pain, migraine, diarrhea,common cold, ischemia, addiction to chemical substances, anxiety,especially preoperative anxiety and different neurological,musculoskeletal, psychiatric and cognition disorders.
 20. Use of aderivative as defined in any one of claims 1 to 14 in the manufacture ofa medicament for use as an adjunct to anesthesia.
 21. A method for thetreatment of hypertension, glaucoma, chronic and pain, migraine,diarrhea, common cold, ischemia, addiction to chemical substances,anxiety, especially preoperative anxiety and different neurological,musculoskeletal, psychiatric and cognition disorders by administering toa subject in need of such treatment an effective amount of a derivativeas defined any one of claims 1 to 14.